Abstract
AIMS: The study attempted to determine the underlying role and regulation mechanism of 3β-hydroxysterol-Δ24 reductase (DHCR24) in the pathophysiology of cerebral small vessel disease-associated cognitive impairment (CSVD-CI). An RNA high-throughput sequencing and independent verification were conducted to identify potential circRNAs becoming the upstream regulator. METHODS: RNA sequencing was performed in whole-blood samples in cohort 1 (10 CSVD-CI and 8 CSVD with cognitively normal [CSVD-CN] patients). The DHCR24 and candidate circRNAs were verified in an independent cohort 2 (45 CSVD-CI participants and 37 CSVD-CN ones). The study also analyzed comprehensive cognitive assessments, plasma molecular index, and brain structure imaging. RESULTS: The expression of DHCR24 and has_circ_0015335 in whole-blood samples of CSVD-CI patients was significantly reduced compared to CSVD-CN patients in RNA sequencing and independent verification. Furthermore, the levels of DHCR24 and has_circ_0015335 were significantly related to global cognitive impairment in CSVD-CI patients. Meanwhile, DHCR24 could regulate the correlation between has_circ_0015335 expression and alterations in brain cortex in surface area, thickness, and volume in CSVD-CI patients. Additionally, hsa_circ_0015335 interacted with DHCR24 for plasma 24(S)-hydroxycholesterol levels among CSVD-CI patients. CONCLUSION: Interaction between DHCR24 and hsa_circ_0015335 cognitively impaired CSVD by affecting brain cholesterol metabolism and brain structural changes.